A. Field of the Invention
The invention pertains to uses of biological response modifying agents. More particularly, this invention relates to the therapeutic use of a polysaccharide substance which is predominantly an acetylated mannan or its derivatives to:
1) relive the symptoms and/or treat the viral diseases of animals, including humans, other mammals, and birds, as well as of plants. These polysaccharidic substances inhibit viral replication either alone, or in combination with other drugs, either through direct antiviral effects or through their immune stimulating activities;
2) enhance the response of the immune system to cancer in humans, other mammals, animals, birds and plants. These polysaccharidic substances stimulate immune cells of the body and directly alter the tumor cell surface so that the stimulated immune cells now recognize the tumor cells as "not self";
3) after the body's response to antigens, toxins, allergens and "self" antigens as seen in autoimmune diseases. These polysaccharidic substances cause immune regulator cells to function more appropriately to achieve homeostasis;
4) act as adjunctive therapy with other drugs in a wide range of conditions where the final step in resolution or cure of the condition requires an immune response. These polysaccharidic substances can be used with anti-infective, antitumor, anti-inflammatory, and antidepressant drugs with no toxicity due to the polysaccharicic substance. The efficacy of the combination is superior over the single drug alone.
B. Description of the General Background Information
Aloe is a member of the lily family. Hardin, Aloes of the World; A Checklist, Index and Code, Excelsa 9:57-94 (1979). Aloe barbadensis Miller is generally recognized as the "true aloe" because of its wide use and, reportedly, most effective healing power, although in Japan, Aloe arborescens Miller traditionally has been used as a folk remedy for various ailments ranging from gastrointestinal disorders to athlete's foot. Aloe vera is a perennial plant with turgid green leaves joined at the stem in a rosette pattern. The leaves of a mature plant may be more than 25 inches long with sawlike spikes along their margins.
Aloe vera contains two major liquid sources, a yellow latex (exudate) and the clear gel (mucilage). The dried exudate of Aloe barbadensis Miller leaves is referred to as aloe. The commercial name is Curacao aloe. It is composed mainly of aloin, aloe-emodin and phenols. Bruce, South African Medical Journal, 41:984 (1967); Morrow et al., Archives of Dermatology, 116:1064-1065 (1980; Mapp et al., Planta Medica, 18:361-365 (1970); Rauwald, Archives Pharmazie, 315:477-478 (1982). A number of phenolics, including anthraquinones and their glycosides, are known to be pharmaceutically active, Bruce, Excelsa, 5:57-68 (1975); Suga et al., Cosmetics and Toiletries, 98:105-108 (1983).
The mucilainous jelly from the parenchymal cells of the plant is referred to as Aloe vera gel. There are generally no anthraquinones to decompose and cause discoloration of the gel unless the gel is contaminated by an improper processing technique. Aloe vera gel is about 98.5% water by weight. More than 60% of the total solid is made up of polysaccharides of carbohydrate origin. Organic acids and inorganic compounds, especially calcium oxalate, account for the remainder of the solid.
Whole leaves, exudates and fresh gels of Aloe plants have been used for a variety of human afflictions. Evidence of their use as a medicinal remedy can be traced to the Egyptians of 400 BC. Aloe vera was also used to embalm the dead, as well as to protect the embalmers from the death-causing agent. Other early civilizations used Aloe vera for skin care, to relieve insect stings and bites, to treat scratches and ulcerated skin, to promote wound healing, to prevent hair loss and as a purgative. It was the traditional medicine of many cultures as an anthelmintic, cathartic and stomachic and was used inter alia for leprosy, burns and allergic conditions. Cole et al., Archives of Dermatology and Syphilology, 47:250 (1943); Chopra et al., Glossary of Indian Medicinal Plants, Council of Scientific and Industrial Research, New Delhi (1956); Ship, Journal of the American Medical Association, 238(16):1770-1772 (1977); Morton, Atlas of Medicinal Plants of Middle American Bahamas to Yucatan, Charles C. Thomas Publisher, 78-80 (1981); Diez-Martinex, La Azbilia, Communicado NO. 46 Sobre Recursos Bioticos Potenticiales del Pais, INIREB, Mexico (1981); Dastur, Medicinal Plants of India and Pakistaon; D. B. Taraporevala Sons & Co., Private Ltd., Bombay 16.17 (1962).
Aloe vera has enjoyed a long history of lay acceptance as possessing "curative" or "healing" qualities. Over the last few years, numerous books and articles meeting scientific standards have been written on Aloe vera. Organizations such as the Aloe Vera Council and recognized medical institutions, through publications and case histories of physicians, veterinarians and other scientists, have given credence to the "aloe phenomenon." Aloe vera has been featured extensively in the field of dermatology, especially for treating radiation-caused skin conditions. Mackee, X-rays and Radium in the Treatment of Diseases of the Skin, 3rd Ed., Lea and Febiger, Phildelphia, 319-320 (1938); Rovatti et al., Industrial Medicine and Surgery, 28:364-368 (1959); Zawahry et al., Quotations From Medical Journals on Aloe Research, Ed. Max B. Skousen, Aloe Vera Research Institute, Cypress, Calif., 18-23 (1977); Cera et al., Journal of the American Animal Hospital Association, 18:633-638 (1982). The body of scientific literature documenting medical applications in digestive problems, as a virucidal, bactericidal and fungicidal agent and in gynecological conditions is extensive and has been adequately reviewed by Grindley et al., Journal of Enthnopharmacology, 16:117-151 (1986)].
Depending on the way the leaves are processes, mucilage and sugars are the major components of the dehydrated gel. The sugars found are galactose, glucose, mannose, rhamnonse, xylose and uronic acids. Although reports conflict, the mucilage is mainly composed of mannan or glucomannan. Eberendu et al., The Chemical Characterization of Carisyn.RTM. (in preparation); Mandal et al., Carbohydrate Research, 86:247-257 (1980b); Roboz et al., Journal of the American Chemical Society, 70:3248-3249 (1948); Gowda et al., carbohydrate Research, 72:201-205 (1979); Segal et al., Lloydia, 31:423 (1968).
Prior to this work, the controversy over the identity of the active substance(s) in Aloe vera had not been settled. It is therefore important to clearly distinguish between the components present in the gel and those found in the exudates. A majority of the gel is a mucilage of mainly polysaccharide nature with minor amounts of various other compounds. It has been observed that in some of the activities there may be some synergistic action between the polysaccharide base and other components. Leung, Excelsa 8:65-68 (1978); Henry, Cosmetics and Toiletries, 94:42-43, 46, 48, 50 (1979). For example, several workers report that the effective components for wound healing may be tannic acid [Freytag, Pharmazie, 9:705 (1954)] and a kind of polysaccharide. Kameyama, Wound-healing compositions from Aloe arborescens extracts. Japanese Patent #7856995, (1979). Mackee, supra, noted that the gel, not the rind or the exudate, was responsible for the beneficial effects in the treatment of radiation burns, and he stressed the importance of using fresh leaves for effective treatment. Polysaccharides degrade with time, and certain molecular weight sizes may be necessary to elicit a specific pharmacological response. Goto et al., Gann, 63:371-374 (1972 ).
However, there are many examples in the literature indicating that polysaccharides can exhibit pharmacological and physiological activities without help from other components. Gialdroni-Grassi, International Archives of Allergy and Applied Immunology, 76(Supp. 1):119-127 (1985); Ohno et al., Chemical and Pharmaceutical Bulletin, 33(6):2564-2568 (1985); Leibovici et al., Chemico-Biological Interactions, 60:191-200 (1986); Ukai et al., Chemical and Pharmaceutical Bellutin, 31:741-744 (1983); Leibovici et al., Anticancer Research, 5:553-448 (1985). One such example relates to development of atherosclerosis. Hyperlipidemia is the general population and especially in familial hypercholesterolemia is associated with coronary heart disease and death. In countries where dietary fiber intake is high, atherosclerosis appear to be uncommon. Trowell et al., Editors, Refined Carbohydrate Foods and Disease, London, Academic Press, 207 (1975). Pectin and guar are reported to lower cholesterol in normal hyperlipidemic patients. Kay et al., American Journal of Clinical Nutrition, 30:171-175 (1977). Locust beam gum, a polysaccharide composed of mannose and galactose, decreased the plasma lipoprotein cholesterol concentrations in both normal and familial hypercholesterolemic subjects. Zavoral et al., American Journal of Clinical Nutrition, 38:285-294 (1983). Addition of guar gum to carbohydrate meals decreased the postprandial rise of glucose in both normal and diabetic subjects. Jenkins et al., Lancet, 2:779-780 (1977). Kuhl et al., in Diabetes Care, 6(2):152-154 (1983) demonstrated that guar gum exhibited glycemic control of pregnant insulin-dependent diabetic patients.
The antitumor activity of polysaccharides has been widely reported. Polysaccharides prepared from Lentinus cyathiformis are known to increase host defense against tumors. Rethy et al., Annales Immunologiae Hungaricae, 21:285-290 (1981). There are several reports that polysaccharides from mushroom, yeast or bacterial extracts can elicit a high degree of host defense activity against viral and tumor infestations. Chihara, Nature, 222:687 (1969); Shwartzman et al., Proceedings of the Society for Experimental Biology and Medicine, 29:737-741 (1932); Suzuki et al., Journal of Pharmacobio-Dynamics, 7(7):492-500 (1984), also reported antitumor activity of a polysaccharide fraction (GF-1) extracted from cultured fruiting bodies of a fungus, Grifola frondosa. This fraction showed equivalent, high levels of inhibiting activity when administered intraperitoneally (IP), intravenously (IV) and intratumorally (IT). However, oral administration (PO) was not effective. The GF-1 fraction also exhibited antitumor action against the solid form of Meth A fibrosarcoma and MM 46 carcinoma in mice. Lentinan, which is a 6-branched .beta.-1-3-liked glucan similar to GR-1, was ineffective against Mech A fibrosarcoma. Chihara, "The antitumor polysaccharide Lentinan: an overview;" Manipulatoin of Host Defense Mechanisms; Ed. by Aoki et al., Excerpta Medica, North Holland, 1-16 (1981); Sasaki et al., Carbohydrate Research, 47(1):99-104 (1976). Synthesized branched polysaccharides were reported to demonstrate activities against tumors. Matsuzaki et al., Makromol. Chem., 186(3):449-456 (1985). Matsuzaki et al. [Makromol. Chem., 187(2):325-331 (1986)] synthesized branched polysaccharides, which showed significant activities, from ivory nut mannan (.beta.-(1-4)-D-mannopyranose) and .beta.-(1-4)-linked glucomannan. A partially acetylated linear .beta.-(1-3)-D-mannan extracted from fruit bodies of Dictyophoria indusiata Fisch, also exhibited antitumor activity. Hara, Carbohydrate Research, 143:111 (1982). It appears that antitumor action depends on the type of polymer main chain and its degree of polymerization, because .beta.-(1-3)-glucan-type polymers show higher antitumor activity than .beta.-(1-4)-glucan and hemicellulosic polymers. Matsuzaki et al., Makromol, Chem., 187:325-331 (1986). A carboxymethylated derivative of .beta.-(1-3)-glucan obtained from bacterial culture filtrate caused severe cell loss from established sarcoma 180 tumors within 2 hours after the injection of the derivative. Baba, Journal of Immunopharmacology, 8(6): 569-572 (1986). The same author observed a compensatory increase in polymorphonuclear leukocytes due to injection of the substance. Incidentally, bestatin, a dipeptide known to possess immune-modulating and antitumor activity [Ishizuka, Journal of Antibiotics, 32:642-652 (1980)], influenced neither the tumor yield nor the polymorphonuclear leukocyte count. Baba et al., supra.
There are numerous reports on the antitumor effect of sulfated polysaccharides, including heparin [Jolles et al., Acta Univ. Int. Cancer, 16:682-685 (1960); Suemasu et al., Gann, 61(2):125-130 (1970)], sulfated laminaran and dextran [Jolles et al., British Journal of Cancer, 17:109-115 (1963)]. Yamamoto et al., in Japanese Journal of Experimental Medicine, 54:143-151 (1984), reported enhancement of antitumor activity of a fucoidan fraction by further sulfation. The sulfated product demonstrated activity against L-1210 leukemia. The authors postulated that the mechanism of the antitumor action might be due partly to inhibition of invasive growth of L-1210 cells, as a result of electrostatic repulsion between the tumor cell and mesothelial cells. Yamamoto et al., supra. Polysaccharides with sulfate groups are also reported to be human T cell mitogens and murine polyclonal B cell activators. Sugawara et al., Microbiological Immunology, 28(7):831-839 (1984). Generally, homopolysaccharides of high molecular weight with sulfate groups possess these properties. Dorries, European Journal of Immunology, 4:230-233 (1974); Sugawara et al., Cell Immunology, 74:162-171 (1982).
It has been reported that glucan extracted from the yeast Saccharamyces cervisiae is a modulator of cellular and humoral immunity. Wooles et al., Science, 142:1078-1080 (1963). The polysaccharide also stimulated proliferation of murine pluripotent hematopoietic stem cells, granulocyte macrophage colony-forming cells and cells forming myeloid and erythroid colonies. Pospisil et al., Experientia, 38:1232-1234 (1982); Burgaleta, Cancer Research, 37:1739-1742 (1977). Maisin et al., [Radiation Research, 105:276-281 (1986)] also reported that IV administration of a polysaccharide induced protection of murine hematopoietic stem cells against x-ray exposure, thereby decreasing the mortality of the mice so exposed.
Lackovic et al., [Proceedings of the Society for Experimental Biology and Medicine, 134:874-879. (1970)], took yeast cell-wall and extracted all constituent matter leaving only "mannans" that he found to be responsible for the induction of .alpha.-interferon production by monocytes. The "purified mannans" alleged to be responsible for the physiologic response had a molecular weight of 5,500-20,000 daltons. He theorized that mannans stimulated mouse peritoneal macrophages to produce the .lambda.-interferon. He also stated that the mannans he isolated showed no toxicity and "they are poor antigens." There was no mention by Lackovic et al., of the use of these "purified mannans" for antiviral activity or for IL-1 stimulation. We submit that Lackovic et al.'s "purified mannans" comprised an assortment of unknown and unidentified substituted and unsubstituted mannans.
Seljelid et al., [Experimental Cell Research, 131(1):121-129 (1981)] have observed that insoluble or gel-forming glycans activated macrophages in vitro, whereas the corresponding soluble glycans did not. They postulated that the orientation in which the glycan was presented to the mononuclear phagocyte was decisive for activation. Bogwald, [Scandinavian Journal of Immunology, 20:355-360 (1984)] immobilized glycans that had a stimulatory effect on the macrophages in vitro. This led the authors to believe that the spatial arrangement of the glycan was decisive for the effect on the macrophages in vitro. A purified polysaccharide isolated from Candida albicans induced an antibody response by human peripheral blood lymphocytes in vitro. Wirz et al., Clinical Immunology and Immunopathology, 33:199-209 (1984). There were significant differences between the anti-Candida antibodies in sera of normal and Candida-infected individuals. Wirz et al., supra.
The antiviral activity of polysaccharides and polysaccharides linked to peptides has been observed. Suzuki et al., Journal of Antibodies, 32:1336-1345 (1979). Suzuki et al,., supra, reported an antiviral action of peptidomannan (KS-2) extracted from mycelial culture of Lentinus edodes. Both oral and intraperitoneal administration increased the peak serum interferon titer, which protected mice against viral infections. This was different from dextran phosphate (DP-40) [Suzuki et al., Proceedings of the Society for Experimental Biology and Medicine, 149(4):1069-1075 (1975)] and 9-methylstreptimidone (9-MS) [Saito et al., Antimier. Agent & Chemotherapy, 10(1):14-19 (1976)], which induced higher titers of interferon in mice only if administered IV or IP.
Anti-inflammatory activity of Aloe vera gel has been widely reported by both oral testimonies and respected scientific journals. Rubel [Cosmetics and Toiletries, 98:109-114 (1983)], discussed fully the possible mechanism of the anti-inflammatory effect of aloe gel. Ukai et al., [Journal of Pharmacobio-Dynamics, 6(12):983-990 (1983)] noted anti-inflammatory activity of polysaccharides extracted from the fruiting bodies of several fungi. The polysaccharides demonstrated a significant inhibitory effect on carrageenan-induced edema. One of the polymers, O-acetylated-D-mannan (T-2-HN), in addition demonstrated a more marked inhibitory effect than phenylbutazone on scald hyperalgesia. Ukai et al., supra. The assertion that the polysaccharide is free from protein and lipids strongly suggests that the anti-inflammatory effect is due to the acetylated mannan only.
Other researchers have also reported anti-inflammatory effects of complex polysaccharides [Saeki et al., Japanese Journal of Pharmacology, 24(1):109-118 (1974)], glycoproteins [Arita et al., Journal of Biochemistry, 76(4):861-869 (1974)] and sulfated polysaccharides [Rocha et al., Biochemical Pharmacology, 18:1285-1295 (1969)].
Literature which reports that polysaccharides possess pharmacological and physiological activities continues to flood the pages of well-respected scientific journals. It is therefore logical that the mucilaginous gel of the Aloe vera plant, which is essentially a polysaccharide, holds the secret to Aloe vera's medicinal properties. The controversy over whether the polysaccharide is a glucomannan, mannan, pectin, or of some other composition, is resolved by a series of chemical purification steps. Yagi et al., [Planta Medica, 31(1):17-20 (1977)], using a slightly modified extraction method; isolated acetylated mannan (aloe mannan) from Aloe arborescens Miller var. natalensis. Ovodova [Khim. Prior. Soedin, 11(1):325-331 (1975)], however, earlier isolated pectin as the main component of the same aloe species. As discussed above, the biological activity of polysaccharides has been recognized for many years. Polysaccharide materials recovered from plants, yeast and bacteria have demonstrated direct biological activity by eliciting an increase in host defense systems. This reaction is primarily manifested by increased host surveillance for other antigenic substances. Polysacchardies serve as adjuvants (DEAE Dextran, etc.) and immunomodulators. They also can function as unique T cell-independent antigens. Both cellular and humoral immunity may be affected, and increased phagocytosis of infectious organisms and tumor cells has been observed, as has enhanced production of immunoglobulins.
The structure of these immunologically active polysacchardies and the types of structural variations appear to be the factors that control their potency and toxicity. Their mode(s) of action remain poorly understood; however, recent evidence indicates that several polysaccharides induce lymphocytes and macrophages to produce a wide range of immunologically active substances. For example, 2-keto-3-deoxy-D-manno-octulosonic acid (KDO) appears to be the chemical portion of lipopolysaccharide (LPS) that provides the minimum signal for macrophage host defense activation [Lebbar et al., Eur. J. Immunol. 16(1):87-91 (1986)]. The composition of the present invention possesses all of the attributes of these immunologically active substances; it is among the most potent of all known biologically active polysaccharides but differs in that no toxicity has been observed. It also manifests specific antiviral activity through alteration of viral glycoprotein synthesis.
A number of pharmacology studies have been conducted on Aloe vera gel in recent times. Results have included more rapid healing of radiation burns [Rowe, J. Am. Pharm. Assoc., 29:348-350 (1940)] and accelerated healing of wounds [Lushbaugh et al., Cancer, 6:690-698 (1953)]. Thermal burns treated with Aloe vera gel heal much faster than untreated burns [Ashley et al., Plast. Reconstr. Surg., 20:383-396 (1957), Rovatto, supra, Rodriguez-Bigas et al., J. Plast. Reconstr. Surg., 81:386-389 (1988)]. The gel is useful in treating leg ulcers [El Zawahry et al., Int. J. Dermatol., 12:68-73 (1973)] and in hastening post surgical healing (Payne, Thesis submitted to Faculty of Baylor University, Waco, Tex. MS Degree). Experimental evidence suggests that extracts of Aloe vera have anti-infectious properties [Solar, Arch. Inst. Pasteur Madagascar, 47:9-39 (1979)] and enhance phagocytosis [Stepanova, Fiziol. Akt. Veshchestva, 9:94-97 (1977)].
The active fraction of Aloe vera gel has been identified by Carrington Laboratories, Inc., Irving, Tex., as a long-chain polyolisperse .beta.-(1,4)-linked acetylated mannan interspersed with O-acetyl groups having a mannose monomer-to-acetyl group ratio of approximately 1:0.91. Acemannan is the nonproprietary name of the biologically active component of Carrisyn.RTM., a compound isolated and developed by Carrington Laboratories, Inc. See U.S. Pat. No. 4,735,935, U.S. Pat. No. 4,851,224, and the U.S. patent application Ser. No. 07/229,164, and references cited therein, the disclosures of all of which are incorporated herein by reference. All of these patents and this patent application are also assigned to Carrington Laboratories, Inc.
Mannans, including glucomannans and galactomannans, have long been used by man. For example, galactomannans, in the form of plant gums, are widely employed as binders for control of food texture. In addition, some mannans have exhibited significant therapeutic properties (Davis and Lewis, eds. Jeanes A., Hodge J., In: American Chemical Society Symposium, Series 15. Washington, D.C., American Chemical Society, 1975). Practitioners of Japanese folk medicine have long believed that extracts of certain fungi have anticancer activity. On investigation, many of these extracts have been found to contain complex carbohydrates with immune-stimulating activity. These carbohydrates are usually polymers of mannose (mannans), glucose (glucans), xylose (hemicellulose(, fructose (levans) and mixtures of these. Individual sugars may be bonded in different ways and chains may be branched or unbranched. Glucans have ben the most widely studies of these immunostimulatory carbohydrates. It has become increasingly clear that even though they have no toxicity mannans are as effective, if not more effective, than glucans.
Pure mannans are relatively uncommon in higher plants, although they are a major structural component of some yeasts. For example, about 45% of the cell wall of Sccharomyces cerevisiae consists of a mannan. This mannan is a water soluble molecule composed of .beta.-(1,6)-, .beta.-(1,3)-, and .beta.-(1,2)-linked, partially phosphorylated D-mannose residues [McMurrough etr al., Biochem. J., 105:189-203 (1967)]. Other biologically active mannans have been obtained from Candida utilis [Oka et al., Gann, 60:287-293 (1969(, Oka et al., Gann, 58:35-42 (1968)], Candida albicans, Coccidioides immitis and Rhodotorulum rubrum [Wheat et al., Infect. Immun., 41:728-734, (1983)]. Mannans (including galactomannans and glucomannans) are relatively resistant to attack by mannosidases but can be degraded by exo- and endo-mannanases [Emi, et al., Agr. Biol. Chem., 36:991-1001 (1972), Snaith, et al., Adv. Carbohydr. Chem. Biochem., 28:401-445, (1973) Herman, Am. J. Clin. Nutr., 24:488-498 (1971), McMaster, et al., Proc. Soc. Exp. Biol. Med., 135:87-90 (1970), Jones et al., J. Biol. Chem. 243:2442-2446 (1968), Eriksson et al., Acta. Chem. Scand., 22:1924-1934 (1968)]. The most marked biological activities of mannans in mammals are activation of macrophages and stimulation of T cells. As a result, they are potent immunostimulants with significant activity against infectious diseases and tumors [Hasenclever et al., J. Immun. 93:763-771 (1964)].
Saccharamyces mannan (15 mg/kg/day) enhances carbon clearance in normal male ddI mice, presumably acting as a reticuloendothelial system stimulant [Suzuki et al., Gann, 62:553-556 (1971)]. This same mannan also increases the number of antibody-forming cells in the spleen [Suzuki et al., Gann, 62:343-352 (1971)]. In vitro studies with mouse peritoneal cells (a mixture of macrophages and lymphocytes) indicate that some mannans and mannan-protein complexes can stimulate interferon release both in vivo and in vitro [lackovic et al., Proc. Soc. Exp. Biol. Med., 134:874-879 (1970)]. The mannans stimulated interferon release in a manner similar to endotoxins but, in contrast to endotoxins, caused minimal toxicity (Borecky et al., Acta Virol., 11:264-266 (1967), Hasenclever, supra). The mannan from Candida albicans is active in this way, but the mannan from Saccharomyces cerevisiae is inactive [DeClercq et al., Ann. NY Acad. Sci., 173:444-461 (1970)]. Inconsistent or poor results have been obtained in other laboratories (DeClercq, supra). These differences may be due to slight structural or size differences in the polymers [Suzuki et al., Jpn. J. Microbiol., 12:19-24 (1968)]. The latter is more likely responsible since low molecular weight mannans (5.5-20 kDa) tend to be most active in the interferon-inducing assay, also Saccharomyces mannan tends to be larger than Candida mannan.
A galactomannan of 20 kDa from Lipomyces starkeyi had weak interferon-inducing properties. In contrast, Candida albicans mannan induced the appearance of interferon activity 2-24 hrs after intravenous administration (Borecky, supra).
DMG, a degraded mannoglucan from Microellobosporia grisea culture fluid, can stimulate cytotoxic activities of macrophages, natural killer (NK) cells and killer T cells, and it enhances the secretion of interleukin-1 (IL-1) and colony-stimulating factors (CSF). It has more potent antitumor activity than lentinan (a glucan from Lentinus edodes) [Nakajima et al., Gann, 75:260-268, (1984), Inoue et al., Carbohyd. Res., 114:164-168 (1983)]. DMG stimulates macrophages to produce increased amounts of IL-1. In addition, DMG enhances 1) antibody production against sheep erythrocytes, 2) natural killer activity of spleen as well as of peritoneal cells, and 3) cytostatic activity of peritoneal macrophages [Nakajima et al., Gann, 75:253-259 (1984)].
Mannose-binding proteins have ben identified in the serum of rabbits and in the liver of humans and laboratory rodents. These proteins can bind glucomannans such as those found in cell walls of bacteria, yeasts, fungi and in envelope glycoproteins of certain viruses such as the human immunodeficiency virus (HIV). In humans, the major mannose-binding protein is an acute-phase protein; its levels rise in stressed individuals [Ezekowitz et al., J. Exp. Med., 169:185-196 (1989)]. The envelope glycoproteins of the human immunodeficiency virus (HIV gp120 and gp41) contain mannose-rich oligosaccharides that appear to be potential ligands for the mannose-binding protein. As a result, the mannose-binding protein can inhibit HIV infection of lymphoblasts and bind selectively to HIV-infected cells. Free yeast mannan can competitively interfere with binding of this protein to infected cells. Thus, factors that induce an increase in the level of the mannose-binding protein may confer protection against HIV.